FR2939436A1 - SYNTHESIS OF MORPHINE-6-GLUCURONIDE OR ONE OF ITS DERIVATIVES - Google Patents

Abstract

The present invention provides a process for the preparation of morphine-6-glucuronide or a derivative thereof comprising the steps of: (ii) reacting a compound of the following formula (I): wherein: R represents a carbonyl group , COR CO or SO R SO with a glucuronic acid derivative corresponding to the following formula (II): in which: PG represents an acetyl, isobutyryl, benzoyl or pivaloyl group, X represents a trihaloacetamidate group, and R represents a group ( C -C) alkylcarboxylate, in the presence of an aromatic solvent and trifluoromethanesulfonyl trimethylsilane (ii) reacting the product obtained in step (i) with a strong basic agent, and (iii) recovering the product obtained in step (ii).

Description

SYNTHESIS OF MORPHINE-6-GLUCURONIDE OR ONE OF ITS DERIVATIVES

FIELD OF THE INVENTION The present invention relates to a process for the preparation of morphine-6-5 glucuronide (M6G) or a derivative thereof.

DESCRIPTION OF THE BACKGROUND OF THE INVENTION Morphine is currently the most used analgesic in the treatment of medium and high intensity pain. This opioid is used in approximately 80% of the 10 cases of acute post-operative pain. Despite its high efficacy, the use of morphine is accompanied by many undesirable side effects characteristic of opioids, such as respiratory depression, nausea, vomiting, inhibition of intestinal transit, dependence and tolerance (Minoru Nariata et al., Pharmacol Et Ther 2001, 89, 1-15). It is known that morphine undergoes an important metabolism which leads in particular to the formation of morphine-6-glucuronide (M6G). This metabolite penetrates weakly into the brain because of its hydrophilic nature. It has more potent analgesic activity than morphine by central administration with decreased respiratory depression, nausea, and vomiting (Paul et al., J. Pharmacol Exp 1989, 251, 477-483; Frances et al J. Pharmacol Exp 1992, 262, 25-31). Patent Application WO95 / 05831 describes the use of M6G in oral form for the treatment of pain. M6G was synthesized in 1968 by Yoshimurai et al. (Yoshimura, H., Oguri, K., Tsukamoto, H. Chem Pharm, Bull, 1968, 16, 2114-2119). On an industrial scale, this method which is based on the Koenigs Knorr principle has a low yield. In addition, trace heavy metals in the final product are difficult to remove. Finally, silver salts must be recycled. It has furthermore been proposed in the patent application WO 99/64430 a process for synthesizing M6G by means of the synthesis of a glycosyl donor in the form of orthoester in the presence of lutidinium perchlorate. However, this method has a low glycosylation yield, of the order of 30%. In addition, these methods which involve glycosylation in a heterogeneous medium with agitation are difficult to implement on an industrial scale. Other embodiments of O-glycosylation have been contemplated, including through activation as an imidate or thioaryl. These embodiments, which require an implementation under particular conditions namely strict anhydricity, that is to say a water content of less than 100 ppm, and low temperature impose significant constraints at the industrial level. In addition, activation via a thioaryl generally uses thiophenol which gives off a problematic foul odor in the context of an industrial scale implementation. There remains therefore a need to have a process for producing such derivatives on an industrial scale, not only with a higher yield but also with a minimum of technical constraints. The object of the present invention is to provide a process for the preparation of M6G or one of its derivatives having a yield of at least 60%, the glycosylation step is carried out in a homogeneous medium, is tolerant to moisture that is to say, supporting a water content of up to 3000 ppm and can be carried out at a temperature of the order of 20 ° C. This object is achieved by the process according to the invention, which comprises the combined use of a glycosylated derivative with a trihaloacetamidate activation as a donor of glycosylated derivatives and of dimorphin derivatives as an acceptor of glycosylated derivatives, making it possible to obtain a very good stereo -sélectivité. We have now found a method allowing satisfactory performance with a minimum of industrial constraints.

Also according to a first aspect, the present invention provides a process for the preparation of M6G or a derivative thereof comprising the steps of: (i) reacting a compound of the following formula (I): wherein: R1 represents a carbonyl group, COR5CO where R5 represents a (C1-C4) alkane-diyl, (C2-C4) alkene-diyl, (C2-C4) alkyne-diyl, hetero (C1-C4) alkanediyl, heterocyclo (C3-C6) group ) alkanediyl, (C 5 -C 14) arene diyl, hetero (C 4 -C 10) arenediyl, bi (C 10 -C 16) arene-oxide diyl, or bi (C 10 -C 16) arene diyl, SO 2 R 6 SO 2 where R 6 is a (C1-C4) alkanediyl, (C2-C4) alkene-diyl, (C2-C4) alkyne-diyl, hetero (C1-C4) alkanediyl, heterocyclo (C3-C6) alkanediyl, (C5 -C14) arene-diyl, hetero (C4-C10) arene-diyl, bi (C10-C16) arene-oxide-diyl or bi (C10-C16) arene-diyl, with a glucuronic acid derivative corresponding to the formula (II) OPG (II) in which: PG represents an acetyl, isobutyryl, benzoyl or piva group; ry, X represents a trihaloacetamidate group, and R4 represents a (C1-C4) alkylcarboxylate group, in the presence of: an aromatic solvent which is unsubstituted or substituted with one or more substituents chosen from the group consisting of a halogen atom, a (C1-C4) alkyl group and a (C1-C4) alkyloxy group, said solvent having a melting point lower than or equal to -20 ° C, and trifluoromethanesulfonyl trimethylsilane (ii) to react the product obtained with step (i) with a strong basic agent, and then (iii) recovering the product obtained in step (ii).

The subject of the present invention is also the compounds corresponding to the following formula (III) in which: R 1 is as defined above, R 2 and R 3 independently represent a PG group as defined previously or a group corresponding to the formula ( IV) below: OPG (IV) wherein: R4 and PG are as defined above, with the proviso that at least one of R2 and R3 is a group of formula (IV).

The subject of the present invention is also the compounds corresponding to the following formula (I): in which: R, is as defined above.

DEFINITIONS In the context of the present invention, the following is meant: a PG group: a protecting group which makes it possible, on the one hand, to protect a reactive function such as a hydroxyl or an amine during a synthesis and, on the other hand, on the other hand, to regenerate the intact reactive function at the end of synthesis; examples of protecting groups as well as methods of protection and deprotection are given in Protective Groups in Organic Synthesis, Green et al., 2nd Edition (John Wiley & Sons, Inc., New York), 1991; there will be mentioned in particular the acetyl, isobutyryl, benzoyl and pivaloyl groups; a halogen atom: a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; a (C 1 -C 4) alkyl group: a substituted or unsubstituted linear or branched saturated aliphatic group having from 1 to 4 carbon atoms; examples that may be mentioned include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl and the like; A hydroxyl group: an OH group; a (C 1 -C 4) alkyloxy group: an O- (C 1 -C 4) alkyl group in which the (C 1 -C 4) alkyl group is as previously defined; a carbonyl group, a C = 0 group; a (C 1 -C 4) alkanediyl group, a divalent linear, branched or cyclic saturated aliphatic group, substituted or unsubstituted, having from 1 to 4 carbon atoms; by way of examples, mention may be made of methane-diyl (-CH2-), ethane-diyl (-CH2-CH2-), propane2,3-diyl (-CH (CH3) CH2-), propanel, 3- diyl (-CH2-CH2-CH2-); and a (C 2 -C 4) alkene diyl group, a linear or branched, mono- or polyunsaturated divalent aliphatic group having from 2 to 4 carbon atoms, comprising, for example, one or two ethylenic unsaturations; by way of examples, mention may be made of ethen-diyl (-CH = CH-), 1-propene-1,3-diyl (-CH 2 -CH = CH-), and the like. a (C2-C4) alkyne-diyl group, a linear or branched, mono- or polyunsaturated divalent aliphatic group having from 2 to 4 carbon atoms, comprising, for example, one or two acetylenic unsaturations; examples that may be mentioned include ethyldiyl (-CEC-), 1-propyne-1,3-diyl (-CEC-CH 2 -) groups; a (C5-C14) arenediyl group, a substituted or unsubstituted divalent cyclic aromatic group preferably having between 5 and 14 carbon atoms; by way of examples, mention may be made of the groups (), - a hetero (C 1 -C 4) alkanediyl group, an alkanediyl group, as defined above, substituted or unsubstituted, preferably having between 1 and 4 carbon atoms, comprising one or more heteroatoms, such as nitrogen, oxygen or sulfur; as examples, mention may be made of the etheroxide-diyl group; a heterocyclo (C3-C6) alkanediyl group, a (C3-C6) cycloalkanediyl group, as defined above, substituted or unsubstituted, preferably having between 3 and 6 carbon atoms, comprising a or more heteroatoms, such as nitrogen, oxygen or sulfur; examples that may be mentioned include oxiranediyl, aziridinediyl, thiranediyl and pyranediyl groups; hetero (C4-C, O) arenediyl group, a divalent cyclic aromatic group preferably having between 4 and 10 carbon atoms and comprising one or more heteroatoms, such as nitrogen, oxygen or sulfur; by way of examples, mention may be made of the groups (~ (S),, - a bi (C 10 -C 16) arene-diyl group, a divalent group comprising two aromatic rings, each of which may be independently substituted or unsubstituted, having preferably from 10 to 16 carbon atoms of examples, mention may be made of group 15),

a bi (C 10 -C 16) aren-oxide diyl group, a divalent group comprising two aromatic rings, each independently substituted or unsubstituted, having from 10 to 16 atoms

Examples of carbon are, for example, the group (

- a - (C1-C4) alkylcarboxylate group, a -CO-O- (C1-C4) alkyl group, the (C1-C4) alkyl group being as defined above. The term "strong basic agent" denotes, in a manner well known to those skilled in the art, any basic agent which dissociates completely in neutral aqueous solution or having at least a high degree of dissociation in neutral aqueous solution. The expression "strong basic agent" refers in particular to sodium hydroxide, potassium hydroxide, lithium hydroxide and ammonium hydroxide. By ambient temperature is meant a temperature of from 20 to 25 ° C. DETAILED DESCRIPTION OF THE INVENTION A compound of formula (I) 1 in which: R1 represents a carbonyl group, COR5CO where R5 represents a (C1-C4) alkanediyl, (C2-C4) alkene-diyl group, (C2- C4) alkyne-diyl, hetero (C1-C1) alkanediyl, (C3-C6) heterocycloalkanediyl, (C5-C14) arene-diyl, hetero (C4-C10) arene-diyl bi (C10-C16) arene-oxide-diyl or bi (C 10 -C 16) arene-diyl, SO 2 R 6 SO 2 where R 6 is (C 1 -C 4) alkanediyl, (C 2 -C 4) alkene diyl, (C 2 -C 4) alkyne-diyl, hetero (C1-C4) alkanediyl, (C3-C6) heterocycloalkanediyl, (C5-C14) arene-diyl, hetero (C4-C10) arene-diyl, bi (C10-C16) arene-oxide-diyl or bi (C10-C16) arene diyl ,. Among the compounds of formula (I), mention may be made in particular of: dimorphin-3-yl terephthalate, dimorphin-3-yl isophthalate, dimorphin-3-yl phthalate, fumarate dimorphin-3-yl, dimorphin-3-yl benzene-1,2-disulfonate, dimorphin-3-yl benzene-1,3-disulfonate, dimorphine thiophene-2,5-dicarboxylate 3-yl, dimorphin-3-yl naphthalene-2,7-dicarboxylate, dimorphin-3-yl 4,4'-oxybenzoate, dimorphin-3-biphenyl-4,4'-dicarboxylate yle, and - dimorphin-3-yl carbonate.

The compound of formula (I) as defined above can be prepared according to various processes, in particular by esterification of the phenol group of morphine with a dicarboxylic acid and removal of water by azeotropic distillation. It can also be prepared according to the method described below. According to a particular embodiment of the process of the present invention, it comprises before step (i), the steps of reacting a compound of formula R, Cl 2 in which R is as defined above with morphine in diphasic medium comprising at least water, a strong basic agent and an aromatic solvent unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a group (C, -C4) alkyl and a (C1-C4) alkyloxy group, said solvent having a melting point of less than or equal to -20 ° C. In this embodiment of preparation of compound of formula (I), the morphine is introduced preferably in excess relative to the compound of formula R, Cl2, for example in a molar ratio of 2.2 moles of morphine to 1 mole of compound R, Cl2, The basic agent used can be strong soda. Among the solvents that can be used in the process as defined above, there may be mentioned in particular chlorobenzene, toluene, 1,2-dichlorobenzene, 1,3,5-trifluorobenzene and mesitylene. Advantageously, chlorobenzene is used which ensures the best solubilization of the reagents.

Advantageously, the mixture of morphine and water is first prepared, to which the strong basic agent is added in an amount making it possible to obtain a pH greater than or equal to 10. The mixture is stirred until a homogeneous solution is obtained . To this homogeneous solution is added the solvent and the compound of formula R, Cl 2, preferably slowly and with strong stirring so as to allow the phase transfer.

The subject of the present invention is also the compounds corresponding to formula (I). These compounds are useful as synthesis intermediates for M6G or its derivatives.

Compound of formula (II) Glucuronic acid derivative having the following formula (II): OPG (II) in which: PG represents an acetyl, isobutyryl, benzoyl or pivaloyl group, X represents a trihaloacetamidate group, and R4 represents a group (Cx1-Cy1) alkylcarboxylate. Among the glucuronic acid derivatives of formula (II), mention may be made in particular of those having one or more of the following characteristics: PG represents an acetyl group, X represents a group -OCNHCI3 or a group -OCNPhCF3, and -R4 represents a methylcarboxylate group.

According to a particular embodiment of the process according to the invention, the glucuronic acid derivative of formula (II) is methyl trichloroacetimidate 2,3,4-tri-O-acetyl-α-D-glucopyranosyluronate. The compound of formula (II) may be prepared according to various methods well known to those skilled in the art.

For example, methyl trichloroacetimidate 2,3,4-tri-O-acetyl-α-D-glucopyranosyluronate may be synthesized according to the method described in the following Scheme 1: Scheme 1 Ac2O pyridine OH OH OAc OAc NaOMe OH MeOH morpholine AcO AcO CC13CN OCNHCCI3 These synthetic processes are described in particular in Chem.Pharm. Bull. 53 (6) 684-687 (2005). for trichloroacetimidate 2,3,4-tri-O-acetyl-α-D-glucopyranosyluronate in J. Chem. Soc. Perkin trans. 1995, for the tri-O pivaloyl derivative and in Liebigs Ann. Chem. 1983, 570-574 for the tri-O-benzoate derivative. Parameters of Step (i) As indicated previously, in the process of the invention, in step (i), a compound of formula (I) is reacted with a glucuronic acid derivative of formula (II) in the presence of an aromatic solvent and trifluoromethanesulfonyl trimethylsilane. Among the aromatic solvents as defined previously that can be used, mention may in particular be made of chlorobenzene, toluene, 1,2-dichlorobenzene, 1,3,5-trifluorobenzene and mesitylene. In particular, chlorobenzene is advantageously used both in step (i) and in the preparation of the compound of formula (I) as indicated above. According to one particular embodiment, the molar ratio of said derivative of formula (II) to said compound of formula (I) is between 2 and 5 and is in particular of 4. The reaction is carried out in the presence of a weak Lewis acid. trifluoromethanesulfonyl trimethylsilane (TMSOTf). The molar ratio of TMSOTf to the compound of formula (I) is between 2.2 and 20 and is in particular 3.1. According to a particular embodiment, the TMSOTf is introduced in two stages: a first part is introduced into the solution of the product of formula (I) in the aromatic solvent prior to the addition of the glucuronic acid derivative, in order to salify the two nitrogens of the compound of formula (I), then the remaining portion is introduced after the addition of the glucuronic acid derivative to ensure 0-glycosylation. The implementation of step (i) leads to the formation of compound corresponding to the following formula (III): (III) in which: R, is as defined above, R2 and R3 independently represent a PG group such that defined above or a group corresponding to the following formula (IV): R OPG (IV) wherein: R4 and PG are as previously defined, provided that at least one of R2 and R3 is a group of formula (IV). The subject of the present invention is also the compounds corresponding to formula (III). These compounds are useful as synthesis intermediates for M6G or its derivatives. Preferably, R 2 and R 3 are both a group of formula (IV). Among the compounds of formula (III) which are subjects of the invention, a first group of compounds have one or more of the following characteristics: R represents a terephthaloyl group; at least one of R2 and R3 represents a group of formula (IV) in which R4 is a methyl 2,3,4-tri-O-acetyl- (3-D-glucuropryranosyluronate) group and PG is Among these compounds, mention may be made in particular of: 6-O-acetylmorphin-3-yl terephthalate and 6-O- (2,3,4-tri-O-acetyl- (3-D) methyl -glucopyranosyluronate) morphin-3-yl, and di (6-O- (2,3,4-tri-O-acetyl- (3-D-glucopyranosyluronate methyl) morphin-3-yl terephthalate.

Parameters of Step (ii) As indicated previously, the product obtained in step (i), ie the compound of formula (III), is reacted with a strong basic agent. According to a particular embodiment, prior to the addition of the strong basic agent, the aromatic solvent is removed, according to methods known to those skilled in the art, for example by extraction of the organic phase optionally completed by evaporation under reduced pressure. . Generally the compound of formula (III) is then dissolved in a hydroalcoholic mixture, for example in a mixture of methanol / water, in a ratio ranging from 20/80 to 80/20, with stirring, until a homogeneous mixture. This mixture is generally cooled to a temperature of less than or equal to 5 ° C. The strong basic agent is then introduced into the mixture generally in an amount which makes it possible to obtain a pH greater than or equal to 10 and in particular greater than or equal to 12.5, preferably keeping the temperature at 5 ° C. at most. According to a particular embodiment, the strong basic agent is sodium hydroxide. The resulting mixture can then be heated, for example, at 20 ° C. for a time sufficient to complete the reaction, for example for one hour. When it is desired to have M6G or one of its derivatives in base form, the mixture, previously cooled for example to a temperature of less than or equal to 5 ° C., is acidified so that it has a pH lower than the pKa of the product to be synthesized, for example at a pH of 5.6. This acidification can in particular be carried out by the addition of hydrochloric acid.

The mixture obtained can then be heated for example at 20 ° C for a time sufficient to complete the reaction for example for 30 minutes. Parameters of step (iii) The product obtained after step (ii) can be recovered as such, that is to say in raw form, for example by filtration and concentration of the filtrate under vacuum. Advantageously, it can be recovered in purified form, which can be carried out according to any purification method known to those skilled in the art, in particular by desalting, where appropriate followed by one or more adsorption and desorption stages on exchange resins. ions then optionally by one or more cycles of dissolution / evaporation / crystallization. In order to reduce the salt content, particularly with a view to eliminating the residual sodium acetate and sodium terephthalate, the filtrate may, for example, be resuspended in alcohol, in particular in methanol under conditions permitting dissolution. M6G or its derivatives for example at 50 ° C for 3 hours, then filter the resulting mixture to remove solid particles and dry the resulting residue for example by evaporation under reduced pressure. The purification can be continued using ion exchange resin. According to a particular embodiment, the residue obtained above is resuspended in demineralized water, and the suspension is acidified to a pH of between 2 and 4 and in particular greater than or equal to 3, for example by addition of sulfuric acid, filtered and the filtrate is brought into contact with a cationic resin under conditions permitting the adsorption of M6G or its derivative, for example with stirring at 20 ° C for 30 minutes, and is then filtered. These operations are repeated until the filtrate is depleted of M6G or its derivative. The resins are then desorbed with a basic solution, for example using ammonia. The basic solution obtained is acidified to a pH of between 5 and 7 and in particular of 6 and then dried for example by evaporation under reduced pressure. Finally, this residue is resuspended in an aqueous-alcoholic mixture, for example in a methanol / water mixture, in a ratio ranging from 20/80 to 80/20, heated under conditions allowing its total dissolution, for example at reflux for 30 minutes. minutes and then the homogeneous mixture is slowly cooled, for example to 0 ° C. in 2 hours, the first crystals appearing at 35 ° C. The crystals are isolated for example on sintered glass, washed for example with methanol, and finally dried for example by heating and evaporation under vacuum. The invention is illustrated in a nonlimiting manner by the examples below.

EXAMPLES

Synthesis Scheme 2 describes the synthesis of the compounds of the intermediate compounds of formula (I) and (III) as well as M6G and its derivatives. In Scheme 2, the starting compounds and reagents, when their method of preparation is not described, are commercially available or described in the literature, or may be prepared according to methods described therein or which are known to those skilled in the art. Scheme 2 R1Cl2 NaOH PhCl / H2O, 25 ° C 1 R4 PGO-N! Glycosylation EXAMPLE 5 The following examples describe the preparation of certain compounds according to the invention. These examples are not limiting and merely illustrate the present invention.

Preparation of Compounds of Formula (I) Example 1 Dimorphin-3-vel Terephthalate at room temperature, to a solution of morphine monohydrate (40.0 g, 0.132 mol) in 0.66N sodium hydroxide (300 mL, 0.198 mol) ) and chlorobenzene (300 mL) is added terephthaloyl chloride (12.0 g, 0.0594 mol) in small portions over 2.5 hours. The reaction medium is stirred for 15 minutes after the end of the addition.

The precipitate formed is filtered and reempted in a mixture of chlorobenzene / 0.66N sodium hydroxide (300 mL / 300 mL) and then washed with water (3 x 250 mL) to obtain dimorphin-3-yl terephthalate in the form of crystals. white (38.2 g, 92%).

1 H NMR (300 MHz, CDCl 3) δ 8.30 (s, 4H, δ-terephthalate), 6.87 (d, 2H, J 8.0 Hz, H-1), 6.67 (d, 2H, J 8.0 Hz, H-2), 5.83 (m, 2H, H-8), 5.32 (m, 2H, H-7), 4.95 (d, 2H, J 6.0 Hz , H-5), 4.20 (m, 2H, H-6), 3.40 (m, 2H, H-9), 3.10 (m, 2H, H-10a), 2.74 (m.p. , 2H, H-14), 2.67-2.61 (m, 2H, H-16a), 2.47 (s, 6H, NCH3), 2.42-2.31 (m, 4H, H- 10b, H-16b), 2.13-2.05 (m, 2H, H-15a), 1.96-1.92 (m, 2H, H-15b).

13 C NMR (75 MHz, CDCl 3)? 163.3 (C = O), 148.8 (C-ipso), 134.3 (C-8), 130.5 (CH terephthalate), 129.7, 128 , 6 (C-ipso), 127.8 (C-7), 126.4 (C-ipso), 121.1 (C-1), 120.0 (C-2), 92.5 (C-1), 5), 65.9 (C-6), 58.9 (C-9), 46.4 (C-16), 43.1 (NCH 3), 42.7 (C-13), 40.5 ( C-14) 35.3 (C-15), 20.9 (C-10).

High Resolution Mass (ES) - Calculated for C42H42N2O8 [M + H2] 2+: m / z = 351.1471 - Found: m / z = 351.1677

In the same way, the compounds of Examples 2 to 11 below were prepared. EXAMPLE 2- Dimorphin-3-yl 3 H-isophthalate 1H NMR (300 MHz, CDCl 3) δ 9.00 (t, 1H, J 1.5 Hz, H-2 '), 8.44 (dd, J 1, 5 Hz, J 8.0 Hz, H-4 ', H-6'), 7.66 (t, 1H, J 8.0 Hz, H-5 '), 6.87 (d, 2H, J 8 , 0 Hz, H-1), 6.67 (d, 2H, 8.0 Hz, H-2), 5.83 (m, 2H, H-8), 5.32 (m, 2H, H -7), 4.95 (d, 2H, J 6.0 Hz, H-5), 4.20 (m, 2H, H-6), 3.40 (m, 2H, H-9), 3 , 09 (m, 2H, H-10a), 2.72 (m, 2H, H-14), 2.66-2.60 (m, 2H, H-16a), 2.47 (s, 6H, NCH 3) , 2.43-2.30 (m, 4H, H-10b, H-16b), 2.15-2.04 (m, 2H, H-15a), 1.95-1.91 (m, 2H). , H-15b). Mass (chemical ionization): [M + H] + = 701.6

Example 3 3H-Dimorphin-3H-Phthalate (300 MHz, CDCl3) δ 7.97 (dd, 2H, 3.5 Hz, J 6.0 Hz, H-3 ', H-6'), 7.67 (dd, J 3.5 Hz, J 6.0 Hz, H-4 ', H-5'), 6.87 (d, 2H, J 8.0 Hz, H-1), 6, 59 (d, 2H, J 8.0 Hz, H-2), 5.74 (m, 2H, H-8), 5.29 (m, 2H, H-7), 4.81 (d, 2H). 6.5 Hz, H-5), 4.15 (m, 2H, H-6), 3.37 (m, 2H, H-9), 3.06 (m, 2H, H-10a). 2.70 (m, 2H, H-14), 2.61-2.56 (m, 2H, H-16a), 2.44 (s, 6H, NCH3), 2.42-2.27 (m, 4H, H-10b, H-16b), 2.08-2.05 (m, 2H, H-15a), 1.80 (m, 2H, H-15b). Mass (chemical ionization): [M + H] + = 701.6 Example 4: Dimorphin-3-dimeric fumarate H NMR (300 MHz, CDCl3) 7.23 (s, 2H, CHCOO) , 81 (d, 2H, J 8.0 Hz, H-1), 6.64 (d, 2H, J 8.0 Hz, H-2), 5.78 (m, 2H, H-8), 5.30 (m, 2H, H-7), 4.95 (d, 2H, J 6.0 Hz, H-5), 4.19 (m, 2H, H-6), 3.42 (m , 2H, H-9), 3.08 (m, 2H, H-10a), 2.74 (m, 2H, H-14), 2.69-2.63 (m, 2H, H-16a) 2.47 (s, 6H, NCH 3), 2.42-2.30 (m, 4H, H-10b, H-16b), 2.16-2.06 (m, 2H, H-15a), 1.92 (m, 2H, H-15b). Mass (chemical ionization): [M + H] + = 651.6 EXAMPLE 5 Dimorphin-3-yl 1 H-NMR-Benzene-1,2-disulfonate (300 MHz, CDCl3) 8 8.24 (dd, 2H, J 3.5 Hz, J 6.0 Hz, H-3 ', H-6'), 7.77 (dd, J 3.5 Hz, J 6.0 Hz, H-4 ', H-5' ), 6.79 (d, 2H, J 8.5 Hz, H-1), 6.51 (d, 2H, J 8.5 Hz, H-2), 5.69 (m, 2H, H-1); 8), 5.22 (m, 2H, H-7), 4.81 (d, 2H, 6.5 Hz, H-5), 4.15 (m, 2H, H-6), 3, (M, 2H, H-9), 3.02 (m, 2H, H-10a), 2.65 (m, 2H, H-14), 2.60-2.54 (m, 2H, H) -16a), 2.41 (s, 6H, NCH3), 2.40-2.22 (m, 4H, H-10b, H-16b), 2.05-2.00 (m, 2H, H- 15a), 1.77-1.72 (m, 2H, H-15b).

Mass (chemical ionization): [M + H] + = 773.6 EXAMPLE 6 Dimorphin-3-yl 1 H-NMR-Benzene-1,3-disulfonate (300 MHz, CDCl3) δ 8.24 (m, 3H, m.p. H-2 ', H-4', H-6 '), 7.78 (t, 1H, 8.5 Hz, H-5'), 6.51 (m, 4H, H-1, H- 2), 5.66 (m, 2H, H-8), 5.27 (m, 2H, H-7), 4.85 (d, 2H, J 6.5 Hz, H-5), 4, (M, 2H, H-6), 3.34 (m, 2H, H-9), 3.03 (m, 2H, H-10a), 2.65 (m, 2H, H-14), 2.61 - 2.55 (m, 2H, H-16a), 2.42 (s, 6H, NCH3), 2.35-2.24 (m, 4H, H-10b, H-16b), 2.09-1.99 (m, 2H, H-15a), 1.79-1.75 (m, 2H, H-15b). Mass (chemical ionization): [M + H] + = 773.6

Example 7 Dimorphin-3-yl Thiophene-2,5-dicarboxylate 1H NMR (300 MHz, CDCl3) δ 7.95 (s, 2H, CH-thiophene), 6.86 (d, 1H, J 8, 0 Hz, H-1), 6.66 (d, 2H, J 8.0 Hz, H-2), 5.79 (m, 2H, H-8), 5.30 (m, 2H, H-1). 7), 4.95 (d, 2H, 6.5 Hz, H-5), 4.18 (m, 2H, H-6), 3.40 (m, 2H, H-9), 3 , 09 (m, 2H, H-10a), 2.75 (m, 2H, H-14), 2.68-2.62 (m, 2H, H-16a), 2.41 (s, 6H, NCH3), 2.40-2.30 (m, 4H, H-10b, H-16b), 2.14-2.05 (m, 2H, H-15a), 1.95-1.90 (m.p. , 2H, H-15b). Mass (chemical ionization): [M + H] + = 708.6 OH EXAMPLE 8 Dimorphin-3-yl NMR-1H-NH 3 -dicarboxylate (300 MHz, CDCl 3) 8.83 (s) , 2H, H-1 ', H-8'), 8.27 (dd, J 1.5 Hz, 8.5 Hz, 2H, H-3 ', H-6'), 8.08 (d. , 2H, J 8.5 Hz, H-4 ', H-5'), 6.92 (d, 1H, J 8.0 Hz, H-1), 6.69 (d, 2H, J 8, 0 Hz, H-2), 5.84 (m, 2H, H-8), 5.34 (m, 2H, H-7), 4.95 (d, 2H, J 6.5 Hz, H- 5), 4.20 (m, 2H, H-6), 3.40 (m, 2H, H-9), 3.11 (m, 2H, H-10a), 2.74 (m, 2H, H-14), 2.68-2.61 (m, 2H, H-16a), 2.47 (s, 6H, NCH3), 2.44-2.32 (m, 4H, H-10b, H -16b), 2.14-2.05 (m, 2H, H-15a), 1.96-1.90 (m, 2H, H-15b). Mass (chemical ionization): [M + H] + = 751.6

Example 9 - Dimorphin-3-yl NMR - H, H NMR (300 MHz, CDCl3) δ 8.16 (d, 4H, J 8.5 Hz, H-2 ', H-6'), 7.14 (d, 4H, J 8.5 Hz, H-3 ', H-5'), 6.87 (d, 2H, J 8.5 Hz, H-1), 6.67 (d, 2H, J 8.5 Hz, H-2), 5.82 (m, 2H, H-8), 5.31 (m, 2H, H-7), 4.95 (d, 2H, J 6, 5 Hz, H-5), 4.20 (m, 2H, H-6), 3.40 (m, 2H, H-9), 3.10 (m, 2H, H-10a), 2, 73 (m, 2H, H-14), 2.66-2.61 (m, 2H, H-16a), 2.42 (s, 6H, NCH3), 2.40-2.30 (m, 4H); , H-10b, H-16b), 2.18-2.10 (m, 2H, H-15a), 1.95-1.90 (m, 2H, H-15b). Mass (chemical ionization): [M + H] + = 793.5 Example 10 Dimorphin-3-yl Biphenyl-4,4'-dicarboxylate 1H NMR (300 MHz, CDCl3) δ 8.25 (d, 4H) , J 8.0 Hz, H-2 ', H-6'), 7.79 (d, 4H, J 8.0 Hz, H-3 ', H-5'), 6.90 (d, 2H) , J 8.0 Hz, H-1), 6.68 (d, 2H, J 8.0 Hz, H-2), 5.84 (m, 2H, H-8), 5.32 (m, 2H, H-7), 4.95 (d, 2H, 6.5 Hz, H-5), 4.22 (m, 2H, H-6), 3.41 (m, 2H, H-9). ), 3.11 (m, 2H, H-10a), 2.74 (m, 2H, H-14), 2.68-2.63 (m, 2H, H-16a), 2.43 (s). , 6H, NCH3), 2.42-2.32 (m, 4H, H-10b, H-16b), 2.17-2.11 (m, 2H, H-15a), 1.95-1, 90 (m, 2H, H-15b).

Mass (chemical ionization): [M + H] + = 777.5

EXAMPLE 11 Dimorphin-3-yl Carbonate OH 1 H NMR (300 MHz, CDCl 3) δ 6.88 (d, 2H, J 8.0 Hz, H-1), 6.59 (d, 2H, J) 8.0 Hz, H-2), 5.70 (m, 2H, H-8), 5.23 (m, 2H, H-7), 4.97 (d, 2H, J 6.5 Hz, H-5), 4.15 (m, 2H, H-6), 3.36 (m, 2H, H-9), 3.11 (m, 2H, H-10a), 2.69 (m, 2H, H-14), 2.68-2.60 (m, 2H, H-16a), 2.43 (s, 6H, NCH3), 2.40-2.27 (m, 4H, H-10b). , H-16b), 2.10-2.04 (m, 2H, H-15a), 1.94-1.90 (m, 2H, H-15b). Mass (chemical ionization): [M + H] + = 597.5

Glycosylation At room temperature, a solution of dimorphin-3-yl terephthalate (50 mg, 0.071 mmol) in chlorobenzene (4 mL) was added TMSOTf (27 μL, 0.15 mmol). The reaction mixture is stirred for 3 min and then methyl 2,3,4-tri-O-acetyl-α-glucopyranosyluronate trichloroacetimidate (171 mg, 0.36 mmol) is added, followed by TMSOTf (13 μL, 0.071 mmol). . The reaction medium is stirred for 0.5 h at room temperature. NaHCO3 (100 mg) is added followed by CH2Cl2 (5 mL) and water (5 mL). The organic phase is separated and dried over Na2SO4.

The solvent is removed under reduced pressure. A mixture of three products: di-O-acetylmorphin-3-yl terephthalate, 6-O-acetylmorphin-3-yl terephthalate and 6-0- (2,3,4-tri-O-acetyl- Methyl 3-D-glucopyranosyluronate) morphin-3-yl and methyl di-6-0- (2,3,4-tri-O-acetyl- (3-D-glucopyranosyluronate)) morphin-3-yl terephthalate in proportions 7:30:63 is obtained.

Purification by preparative reversed-phase chromatography (gradient (H 2 O + 0.1% TFA) -CH 3 CN of 95: 5 at 20:80) makes it possible to isolate the three species.

Example 12 Di (6-O-acetylmorphin-3-yl) -NH-NMR terephthalate (300 MHz, CDCl3) S 8.30 (s, 4H, CH terephthalate), 6.91 (d, 2H, J 8.0 Hz, H-1), 6.66 (d, 2H, J 8.0 Hz, H-2), 5.67 (m, 2H, H-8), 5.46 (m, 2H, H-7). ), 5.15 (m, 4H, H-5, H-6), 3.43 (m, 2H, H-9), 3.10 (m, 2H, H-10a), 2.81 (m , 2H, H-14), 2.67 (m, 2H, H-16a), 2.47 (s, 6H, NCH 3), 2.43-2.34 (m, 4H, H-10b, H -16b), 2.14-1.91 (m, 10H, CH3CO, H-15).

13 C NMR (75 MHz, CDCl 3)? 170.4, 163.2 (C = O), 149.5, 133.6, 132.5, 131.8, 131.6 (C-ipso), 130.3. (CH-terephthalate), 129.2 (C-7), 128.7 (C-8), 121.9 (C-1), 119.5 (C-2), 88.7 (C-5) , 68.0 (C-6), 58.9 (C-9), 46.5 (C-16), 42.8 (NCH3), 42.7 (C-13), 40.3 (C 14) 35.0 (C-15), 20.8 (C-10), 20.6 (CH3CO). High Resolution Mass (ES) - Calculated for C46H46N2O10 [M + H2] 2+: m / z = 393.1576 - Found: m / z = 393.1560 Example 13- 6-O-acetylmorphin-3-yl terephthalate and methyl 6-0- (2,3,4-tri-O-acetyl-13-D-glucopyranosyluronate) morphin-3-yl 1 H NMR (300 MHz, CDCl3) δ 8.31 (m, 4H, m.p. CH-terephthalate), 6.89 (m, 2H, H-1, H-1 '), 6.65 (m, 2H, H-2, H-2'), 5.77 (m, 1H, H -8 '), 5.68 (m, 1H, H-8), 5.46 (m, 1H, H-7), 5.33 (m, 1H, H-7'), 5.19 (m , 2H, H-3 ", H-4"), 5.15 (m, 1H, H-6), 4.96 (m, 3H, H-2 ", H-5, H-5 '), 4.86 (d, 1H, 7.5 Hz, H-1 "), 4.31 (m, 1H, H-6 '), 4.05 (m, 1H, H-5"), 3.72 ( s, 3H, OCH3), 3.48 (m, 2H, H-9, H-9 '), 3.11 (m, 2H, H-10a, H-10a'), 2.85-2.65. (m, 4H, H-14, H-14 ', H-16a, H-16a'), 2.52-2.37 (m, 10H, NCH3, H-10b, H-10b ', H-16b , H-16b '), 2.15-1.85 (m, 13H, H-15, H-15', CH3CO), 1.73 (s, 3H, CH3CO).

13C NMR (75 MHz, CDCl3)? 8,170.4, 170.1, 169.4, 169.0, 167.3, 163.6, 163.3 (C = O), 150.4, 149.5 133 , 7, 133.6 (C-ipso), 132.0, 131.6, 130.8, 130.6, 130.3, 129.0, 128.9 (CH-terephthalate, C-8, C-8 C-7, C-7 ', C-ipso), 122.2, 122.0 (C-1, C-1'), 119.6, 119.3 (C-2, C-2 ' ), 99.3 (C-1 "), 89.8, 88.7 (C-5, C-5 '), 73.7 (C-6'), 72.7 (C-5"), 71.8 (C-3 "or C-4"), 71.0 (C-2 "), 69.4 (C-3" or C-4 "), 67.9 (C-6), 59 , 0, 58.8 (C-9, C-9 '), 46.6, 46.3 (C-16, C-16'), 42.8 (NCH3), 40.6, 40.2 ( C-14, C-14 ') 35.2, 34.9 (C-15, C-15'), 21.2, 21.0, 20.7, 20.6, 20.5, 20.4 (C-10, C-10 'CH3CO).

High Resolution Mass (ES) - Calculated for C57H60N2018 [M + H2] 2+: m / z = 530.1921 - Found: m / z = 530.191825 Example 14- Di (6-0) terephthalate Methyl 4-tri-O-acetyl- (3-D-glucopyranosyluronate) 3-morphin-1H NMR (300 MHz, CDCl3) δ 8.34 (s, 4H, CH terephthalate), 6.90 (d , 2H, J 8.0 Hz, H-1), 6.63 (d, 2H, J 8.0 Hz, H-2), 5.77 (m, 2H, H-8), 5.34 ( m, 2H, H-7), 5.23 (m, 4H, H-3 ', H-4'), 5.02-4.94 (m, 4H, H-2 ', H-5), 4.86 (d, 2H, 7.5 Hz, H-1 '), 4.32 (m, 2H, H-6), 4.06 (d, 2H, J 9.5 Hz, H-5). 3.72 (s, 6H, OCH 3), 3.48 (m, 2H, H-9), 3.11 (m, 2H, H-10a), 2.75-2.60 (m, 4H, H-14, H-16a), 2.51-2.25 (m, 10H, NCH3, H-10b, H-16b), 2.16-1.90 (m, 16H, H-15, CH3CO) 1.75 (s, 6H, CH3CO).

13 C NMR (75 MHz, CDCl 3) δ 170.0, 169.4, 169.3, 167.4, 163.9 (C = O), 150.4, 133.7, 132.5, 131.7, 131.4 (C-ipso), 130.6 (CH terephthalate, C-8), 128.9 (C-7), 122.0 (C-1), 119.3 (C-2), 99 , 2 (C-1 '), 88.7 (C-5), 73.6 (C-6), 72.9 (C-5'), 71.7 (C-3 'or C-4' ), 70.9 (C-2 '), 69.4 (C-3' or C-4 '), 58.8 (C-9), 52.9 (OCH 3), 46.2 (C-16) ), 43.1 (NCH3), 41.1 (C-14), 35.7 (C-15), 21.0 (C-10), 20.6, 20.5, 20.4 (CH3CO) .

High Resolution Mass (ES) - Calculated for C68H74N2O26 [M + H2] 2+: m / z = 667.2265 - Found: m / z = 667.2253

Saponification of intermediates resulting from the coupling of oligosaccharides After treatment and extraction of the organic phase (chlorobenzene) resulting from the coupling, the chlorobenzene is evaporated under reduced pressure (15 mbar) to obtain a brownish oil (m = 47.4 g). To this oil is added a mixture of methanol (140 ml) and deionized water (35 ml) at 30 ° C., with stirring until a homogeneous mixture is obtained. The mixture is then cooled to -5 ° C. To this mixture, 62.5 ml of a concentrated sodium hydroxide solution (30% w / w) is added not exceeding a temperature of 5 ° C in the reactor. This mixture (pH = 12.72) is then heated at 20 ° C for 1 h under nitrogen and then cooled to -3 ° C. To the mixture thus obtained, 37 ml of a solution of hydrochloric acid (37% HCl) are added (pH = 5.6). The mixture is heated to 20 ° C and maintained at this temperature for 30 minutes (pH stable at 5.6). The mixture is then filtered and the filtrate obtained is concentrated under vacuum (15 mbar) to obtain a solids content of 67.0 g.

Purification of the residue resulting from saponification and acidification This residue is suspended in 500 ml of methanol at 50 ° C. for 3 hours (desalting) to obtain, after filtration and evaporation under reduced pressure (15 mbar), a residue of 30.8 g comprising mixture of morphine analyzed in HPLC (about 30%) and M6G (around 70%). The residue obtained above is suspended in 100 ml of demineralized water and the suspension obtained is acidified to a pH equal to 3.58 with 98% H 2 SO 4 (2 ml) and then filtered. To the filtrate is added 6 g of the resin sold under the name IRP 20 69 by the company Rohm and Hass (in a weight ratio of 3 relative to the weight of M6G contained according to the estimate obtained by HPLC). The heterogeneous mixture thus obtained is stirred at 20 ° C. for 30 minutes and then filtered. The operation is repeated until the M6G content is exhausted. The resins obtained are desorbed with dilute ammonia (3% NH 4 OH) and the resulting basic solution (pH = 10.9) is neutralized to a pH of about 5 to 6 with dilute HCl. The acidic aqueous solution obtained is evaporated under reduced pressure (15mbar) to obtain a dry residue of 5.6 g. It is identified in H.P.L.0 (M6G content of the order of 80%). 30 Recrystallization of M6G

The previous dry residue (5.55 g) was suspended in a mixture of water (166.5 ml) and methanol (277.5 ml). The mixture is heated at reflux (90 ° C) for 30 minutes and then cooled to 0 ° C in 2 hr. The first crystals are formed at 35 ° C. The crystals are isolated on fritted glass and then washed with 5 ml of methanol. After drying at 80 ° C. under 15 mbar, 2.6 g of pure M6G (organic purity> 99%) are isolated. 16 17 N HPLC (M6G content) = 98.6%

Mass (chemical ionization) = [M + H] + = 462.2

13 C NMR (75 MHz, CDCl3) (D2O / NaOD exchange) b (ppm +/- 0.01 ppm): 129.71, 127.42 (Cl, C2); 155, 73, 149.25 (C3, C4); 98.19 (C5); 111, 12 (C1 '); 85.82, 85.17, 82.94, 82.77, 81.40 (C6, C2 ', C3', C4 ', C5'); 68.66 (C9); 55.76 (C16); 52.07 C13); 50.79 (C17); 48.34 (C14); 42.80 (C15); 30.70 (C10); 185.30 (CO2H)

Claims (14)

REVENDICATIONS1. A process for the preparation of morphine-6-glucuronide or a derivative thereof comprising the steps of: (i) reacting a compound of the following formula (I): wherein: R1 represents a carbonyl group, CORSCO where R5 is (C1-C4) alkanediyl, (C2-C4) alkene-diyl, (C2-C4) alkyne-diyl, hetero (C1-C4) alkanediyl, heterocyclo (C3-C6) alkanediyl, (C5 -C14) arene-diyl, bi (C10-C16) arene-oxydediyl, bi (C10-C16) arene-diyl, or hetero (C4-C10) arene-diyl, SO2R6SO2 where R6 represents a (C1-C4) alkane group -diyl, (C2-C4) alkene-diyl, (C2-C4) alkyne-diyl, hetero (C1-C4) alkane-diyl, heterocyclo (C3-C6) alkane-diyl, (C5-C14) arene-diyl, hetero (C4-C10) arene diyl, bi (C10-C16) arene-oxide-diyl or bi (C10-C16) arene-diyl, with a glucuronic acid derivative having the following formula (II): OPG ( II) in which: PG represents an acetyl, isobutyryl, benzoyl or pivaloyl group; X represents a trihalogeno group; acetamidate, and R4 represents a (C1-C4) alkylcarboxylate group, in the presence of: - an aromatic solvent unsubstituted or substituted with one or more substituents selected from the group consisting of a halogen atom, a (C1-C4) group ) alkyl and a (C1-C4) alkyloxy group, said solvent having a melting point lower than or equal to -20 ° C, and trifluoromethanesulfonyl trimethylsilane (ii) reacting the product obtained in step (i) with a strong basic agent, and then (iii) recovering the product obtained in step (ii). 2. Method according to claim 1, wherein prior to step (i), reacting a compound of formula R, Cl2 in which R, is as defined in claim 1, with morphine in diphasic medium comprising at least less than water, a strong basic agent and an aromatic solvent unsubstituted or substituted by one or more substituents selected from the group consisting of a halogen atom, a (C 1 -C 4) alkyl group and a (C, -C4) alkyloxy, said solvent having a melting point less than or equal to -20 ° C. 3. Process according to claim 1 or 2, characterized in that said compound of formula (I) is chosen from the group consisting of: dimorphin-3-yl terephthalate, dimorphin-3-yl isophthalate, - dimorphin-3-yl phthalate, - dimorphin-3-yl fumarate, - dimorphin-3-yl benzene-1,2-disulfonate, - dimorphin-3-benzene-1,3-disulfonate yle, - dimorphin-3-yl thiophene-2,5-dicarboxylate, - dimorphin-3-yl naphthalene-2,7-dicarboxylate, dimorphin-3-yl 4,4'-oxybenzoate, - dimorphin-3-yl biphenyl-4,4'-dicarboxylate, and dimorphin-3-yl carbonate. 4. Method according to any one of the preceding claims, characterized in that said compound of formula (II) has one or more of the following characteristics: PG represents an acetyl group, X represents a group -OCNHCI3 or a group -OCNPhCF3 and R4 represents a methylcarboxylate group. 5. Method according to any one of the preceding claims, characterized in that said compound of formula (II) is methyl trichloroacetimidate 2,3,4-tri-O-acetyl-α-D-glucopyranosyluronate. 6. Method according to any one of the preceding claims, characterized in that said aromatic solvent is selected from chlorobenzene, toluene, 1,2-dichlorobenzene, 1,3,5-trifluorobenzene and mesitylene. 7. Method according to any one of the preceding claims, characterized in that said strong basic agent is sodium hydroxide. 8. Process according to any one of the preceding claims, characterized in that the molar ratio of said glucuronic acid derivative of formula (II) to said compound of formula (I) is between 2 and 5. 9. Process according to any one of the preceding claims, characterized in that the molar ratio of trifluoromethanesulfonyl trimethylsilane to said compound of formula (I) is between 2.2 and 20. 15 A compound of the formula WhereRiO (III) in which: R is as defined in Claim 1, R2 and R3 independently represent a PG group as defined in Claim 1 or a group of the following Formula (IV): OPG (IV) Wherein: R4 and PG are as defined in claim 1 with the proviso that at least one of R2 and R3 is a group of formula (IV). 11. Compound according to claim 10, characterized in that it has one or more of the following characteristics: - R, represents a terephthaloyl group, - at least one of R2 and R3 represents a group of formula (IV) in which R4 is a methyl 2,3,4-tri-O-acetyl-8-D-glucuropryranosyluronate group and PG 5 is an acetyl group. 12. A compound according to claim 10 or 11, characterized in that it is selected from the group consisting of: 6-O-acetylmorphin-3-yl terephthalate and 6-0- tri-O-acetyl-3-D-10 methyl glucopyranosyluronate) morphin-3-yl, and - di 6-O- (2,3,4-tri-O-acetyl- (3-D-glucopyranosyluronate) terephthalate; methyl) morphin-3-yl. 13. A compound of formula WhereR 1 O 1 in which: R 1 is as defined in claim 1. A compound according to claim 13 selected from the group consisting of: dimorphin-3-yl terephthalate, dimorphin-3-yl isophthalate, dimorphin-3-yl phthalate, fumarate dimorphin-3-yl, dimorphin-3-yl benzene-1,2-disulfonate, dimorphin-3-yl benzene-1,3-disulfonate, thiophene-2,5-dicarboxylate, dimorphin-3-yl, dimorphin-3-yl naphthalene-2,7-dicarboxylate, dimorphin-3-yl 4,4'-oxybenzoate, dimorphin-2-biphenyl-4,4'-dicarboxylate 3-yl, and dimorphin-3-yl carbonate.